The therapeutic potential of gene transfer as a treatment for retinal disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be considered for clinical application. The overall goal of our research effort is to prevent or delay the course of blindness in patients. Our work focuses on the group of inherited blinding diseases called Retinitis Pigmentosa. Currently, there is no widely accepted or effective preventive treatment for this family of retinal degenerations. The goal of this project is to test neurotrophic factors for their ability to "rescue" photoreceptors from retinal degeneration. Viral vectors derived from adeno-associated virus (AAV) and feline immunodeficiency virus (FIV) will be used for transfer of neurotrophin genes to the retina. Gene transfer methods will be evaluated in several rodent models of retinal degeneration (light damage, RCS, opsin mutations). In these rodent models, cell death is attributed to several different mechanisms. Our underlying premise is that transfer to the retina of neurotrophin genes will protect against cell death, and delay the photoreceptor and RPE loss in retinal degeneration. In previous studies, we established that expression of Neurotrophic factors in the retina could slow the degeneration in rodent models of retinal disease. In specific aim 1, we propose to optimize the rescue effect of neurotrophic factors and combinations of factors using vectors incorporating inducible promoters to optimize the temporal expression and dose. In specific aim 2, we will increase the efficiency of retinal gene transfer through modifying the viral tropism of the AAV vector and development of new vectors targeted to specific classes of retinal cells. In specific aim 3, we will optimize the survival of cone photoreceptors in these disease models using targeted and controlled expression of neurotrophic factors. We will apply the same paradigm of detailed anatomical and functional (ERG) characterization for evaluating the rescue effect that has worked well in previous experiments. In summary, this application supports key, initial "proof-of-principle" experiments to create retina-specific viral vectors and systems to transfer neurotrophic factors for gene therapy of retinal degeneration.